genetic and environmental factors contribute to the aetiology of MS.
More than 50 genomic regions have been associated with MS susceptibility
and vitamin D status also influences the risk of this complex disease.
However, how these factors interact in disease causation is unclear. We
aimed to investigate the relationship between vitamin D receptor (VDR) binding in lymphoblastoid (lymphocyte/white blood cell tumours) cell lines (LCLs), chromatin
states in LCLs and MS associated genomic regions. Using the Genomic
Hyperbrowser, we found that VDR binding regions overlapped with active
regulatory regions (active promoter (AP) and strong enhancer (SE)) in
LCLs more than expected by chance (45.3 fold enrichment for SE
(p<2.0e-05) and 63.41 fold enrichment for AP (p<2.0e-05)).
Approximately 77% of VDR regions were covered by either AP or SE
elements. The overlap between VDR binding and regulatory elements was
significantly greater in LCLs than in non-immune cells (p<2.0e-05).
VDR binding also occurred within MS regions more than expected by chance
(3.7 fold enrichment, p<2.0e-05). Furthermore, regions of joint
overlap SE-VDR and AP-VDR were even more enriched within MS regions and
near to several disease associated genes.These findings provide relevant
insights into how vitamin D influences the immune system and the risk
of MS through VDR interactions with chromatin state inside MS regions.
Furthermore, the data provides additional evidence for an important role
played by B cells in MS.
|Vitamin D receptor
"The evidence is overwhelming that vitamin D deficiency increases the risk of developing MS. The question is how? Vitamin D can act in the genome by binding to its own receptor called the vitamin D receptor or VDR. We have previously mapped out where in the genome the VDR binds. Here we are trying to understand the function of VDR binding. The majority of vitamin D binding sites are at gene regulatory sites; the probability of this happening by chance is extremely low- i.e. vitamin D is playing an active role in regulating genes. Secondly of the 60 or so genes associated to MS, we show hear that nearly 80% of them are regulated by vitamin D, again the probability of this being a chance finding is smaller than the chances of one of us winning the lottery. It seems clear that vitamin D influences the risk of getting MS through gene-environment interactions. So now the question is- for people at high risk of getting the disease (for example carrying all the risk genes) can we give them high dose vitamin D to prevent them from ever getting MS? I hope so."
CoI: This work was done by some members of Team G
Labels: Chromatin, Vitamin D